Triptolide attenuates renal interstitial fibrosis in rats with unilateral ureteral obstruction

Yuan, Xianxian; He, Xiaoshun; Wang, Chang Xi; Liu, Long Shan; Qian, Fu

doi:10.1111/j.1440-1797.2010.01359.x

Cited by 35 publications

(20 citation statements)

References 29 publications

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“…Triptolide has entered human studies in patients with ADPKD (see clinicaltrials.gov). Triptolide attenuates renal interstitial fibrosis in rats with unilateral ureteral obstruction (Yuan et al, 2011). Triptolide can dramatically attenuate albuminuria and renal lesion accompanied with dyslipidemia and obesity in db/db diabetic mice (Gao et al, 2010), and in experimental membranous nephropathy, triptolide decreases reactive oxygen species and p38 MAPK (Chen et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Triptolide reduces cyst growth in autosomal dominant polycystic kidney disease (ADPKD) (Leuenroth et al, 2007), decreases experimental membranous nephropathy (Chen et al, 2010) and podocyte injury (Zheng et al, 2008), and attenuates diabetic nephropathy in rodents (Gao et al, 2010). Triptolide decreases interstitial fibrosis in a model of unilateral kidney obstruction (Yuan et al, 2011). The effect of triptolide on AKI is not known.…”

Section: Introductionmentioning

confidence: 99%

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The Water-Soluble Triptolide Derivative PG490-88 Protects against Cisplatin-Induced Acute Kidney Injury

Kim

Ravichandran

Özkök

et al. 2014

J Pharmacol Exp Ther

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Triptolide, a traditional Chinese medicine, has anti-inflammatory, antiproliferative, and proapoptotic properties. As interstitial inflammation and tubular apoptosis are features of cisplatin-induced acute kidney injury (AKI), we determined the effect of the watersoluble triptolide derivative 14-succinyl triptolide sodium salt (PG490-88) in a mouse model of cisplatin-induced AKI. PG490-88 resulted in a significant decrease in blood urea nitrogen (BUN), serum creatinine, and acute tubular necrosis (ATN) score, and a nonsignificant increase in tubular apoptosis score in AKI. The mitogen-activated protein kinase (MAPK) pathway is activated in AKI. On immunoblot analysis, phosphoextracellular signal-regulated kinase (p-ERK) was increased 3.6-fold in AKI and 2.0-fold inhibited by PG490-88. Phospho-c-Jun N-terminal kinase (p-JNK) was increased in AKI. PG490-88 resulted in a nonsignificant decrease in p-JNK. Phospho-p38 was not affected by cisplatin or PG490-88. MAPK phosphatase-1 (MKP-1) that negatively regulates MAPK signaling has not previously been studied in AKI. MKP-1 activity was not affected by cisplatin or PG490-88. Changes in p-ERK, p-JNK, and MKP-1 were confirmed on reverse protein phase analysis. The ERK inhibitor U0126 resulted in lower BUN and serum creatinine, suggesting a mechanistic role of ERK in AKI. The increase in interleukin-1a (IL-1a), IL-1b, IL-6, CXCL1, and IL-33 in the kidney in AKI was unaffected by PG490-88. In summary, PG490-88 protects against AKI and ATN despite no decrease in tubular apoptosis. The protection of PG490-88 against AKI was associated with a decrease in p-ERK and was independent of MKP-1 and proinflammatory cytokines. In conclusion, PG490-88 protects against cisplatin-induced AKI possibly by decreasing p-ERK.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Water-Soluble Triptolide Derivative PG490-88 Protects against Cisplatin-Induced Acute Kidney Injury

Kim

Ravichandran

Özkök

et al. 2014

J Pharmacol Exp Ther

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“…24,45,46 Indeed, the mRNA expression levels of collagen 1A2, PAI-1, fibronectin, and MCP-1 in the kidneys were significantly elevated in mice with 3 days' UUO compared with normal mice ( Figure S1). No inhibitory effects on the elevated mRNA expression levels of the profibrotic genes, however, were obtained with 17864-ULSlysozyme and the low-dose sunitinib.…”

Section: Inhibitory Effects On Downstream Profibrotic Factorsmentioning

confidence: 99%

Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

Dolman¹,

Harmsen²,

Pieters³

et al. 2012

IJN

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Background: Activated proximal tubular cells play an important role in renal fibrosis. We investigated whether sunitinib and a kidney-targeted conjugate of sunitinib were capable of attenuating fibrogenic events in tubulointerstitial fibrosis. Methods: A kidney-targeted conjugate was prepared by linkage of a sunitinib analog (named 17864) via a platinum-based linker to the kidney-specific carrier lysozyme. Pharmacological activity of 17864-lysozyme was evaluated in human kidney proximal tubular cells (HK-2); the capability of the kidney-directed conjugate to accumulate in the kidneys was studied in mice. Potential antifibrotic effects of a single-dose treatment were evaluated in the unilateral ureteral obstruction (UUO) model in mice. Results: The 17864-lysozyme conjugate and its metabolites strongly inhibited tyrosine kinase activity. Upon intravenous injection, 17864-lysozyme rapidly accumulated in the kidneys and provided sustained renal drug levels for up to 3 days after a single dose. Renal drug level area under the curve was increased 28-fold versus an equimolar dose of sunitinib malate. Daily treatment of UUO mice with a high dose of sunitinib malate (50 mg/kg) resulted in antifibrotic responses, but also induced drug-related toxicity. A single dose of 17864-lysozyme (equivalent to 1.8 mg/kg sunitinib) was safe but showed no antifibrotic effects. Conclusion: Multikinase inhibitors like sunitinib can be of benefit in the treatment of fibrotic diseases, provided that their safety can be improved by strategies as presented in this paper, and sustained renal levels can be achieved.

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“…34 Triptolide has been shown to attenuate kidney fibrosis in a rat unilateral ureteric obstruction model. 35 Saikosaponins have been reported to have antifibrotic effects in liver disease and to inhibit mesangial cell proliferation and matrix synthesis. [36][37][38] Rhein (an acidic compound derived from rhubarb) has been observed to decrease levels of kidney extracellular matrix and TGFb1/fibronectin in diabetic db/db mice.…”

Section: Antifibrotic Effects Of Traditional Medicinesmentioning

confidence: 99%

Recent Advances in Traditional Chinese Medicine for Kidney Disease

Zhong

Menon

Deng

et al. 2015

American Journal of Kidney Diseases

118

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Triptolide attenuates renal interstitial fibrosis in rats with unilateral ureteral obstruction

Abstract: Trip significantly attenuated tubulointerstitial fibrosis in a rat UUO model and the effect of Trip on renal fibrosis was similar to that of MMF. Trip may be useful as a potential candidate in the treatment of renal fibrosis.

Cited by 35 publications

References 29 publications

The Water-Soluble Triptolide Derivative PG490-88 Protects against Cisplatin-Induced Acute Kidney Injury

The Water-Soluble Triptolide Derivative PG490-88 Protects against Cisplatin-Induced Acute Kidney Injury

Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

Recent Advances in Traditional Chinese Medicine for Kidney Disease

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